Experts say future of glaucoma treatment may lie in sustained release

“As we are able to diagnose glaucoma earlier and earlier and have a better understanding of the disease, it will help to determine the most appropriate therapy for the individual patient, whether that is drops, sustained release or surgical intervention,” private practitioner Chris Wroten, OD, told Primary Care Optometry News.

He explained how the multitude of treatment modalities in development for a number of conditions, including glaucoma, have the potential to greatly improve patient outcomes and quality of life, recently at SECO in New Orleans.

Compliance is a major known hurdle to treatment, and the industry is working to gain FDA approval for new platforms and drug delivery systems in this sector using sustained release therapies.

There is a clear need for alternative glaucoma drug delivery to improve medication adherence rates in patients, according to a February 2019 Ocular Surgery News article featuring James D. Brandt, MD, director of glaucoma service at Tschannen Eye Institute at the University of California, Davis.

“Sustained release platforms, whether as part of an external or internal delivery system, are necessary to improve glaucoma medication adherence,” Brandt said. “The platforms must properly balance efficacy and duration with safety, ease of use, reversibility and other factors to be effective solutions for glaucoma patients.”

Wroten believes that optometrists are constantly aware of the impact the preservatives in topical drops have on the ocular surface of the eye. “If we can get medication into the eye in a better way or can lower IOP effectively via another novel method, it would certainly be a win for patients,” he said.

According to a 2015 Ophthalmology study cited in the OSN article, more than 50% of glaucoma patients are nonadherent with their eye drop medications.

“Patients don’t always use every dose they are supposed to,” Danica Marrelli, OD, FAAO, DiplAAO, clinical professor and assistant dean of clinical education at University of Houston College of Optometry, said in an interview with PCON. “Glaucoma is pretty asymptomatic. Patients do not feel any better or see any better when they take the drops, and there are many reasons patients don’t take their medications.”

Sarah Dougherty Wood, OD, MS, FAAO, DiplABO, clinical assistant professor of ophthalmology and visual sciences at Kellogg Eye Center at University of Michigan, told PCON that by 2020, there will be 80 million people worldwide with glaucoma, according to research from Colin Cook, FCS(Ophth)SA, and Paul Foster, FRCOphth. She noted that the Glaucoma Adherence and Persistence Study (GAPS) found that only 10% of patients had filled their prescriptions continually at 1 year, using pharmacy refill rates.

Wood added that research has shown that, for the end-stage glaucoma patient, the direct cost per year is more than $2,500, and the majority of that is medication cost.

Ike K. Ahmed, MD, a glaucoma surgeon, speaker and researcher, also believes new drug delivery technologies will assist clinicians in treating noncompliant glaucoma patients and he spoke about the new technologies at SECO in New Orleans.

“By getting patients to a lower IOP and keeping them lower, it’s a good place for them to be,” Ahmed said during the keynote presentation. “We can push back their time of visual disability by intervening earlier and getting them lower, and that will have a greater effect throughout a patient’s lifespan.”

New technologies on the horizon

A number of therapies are at various points in FDA clinical trials.

Wood said the follow-up timing might not be an issue for the platform, as she already sees her glaucoma patients about every 3 to 4 months for pressure checks.

Intended for use in open-angle glaucoma, Bimatoprost SR from Allergan is an intracameral injection into the anterior chamber. Its rod-shaped pellet, when in the anterior chamber, looks like a piece of rice, Wood said. It sits inferiorly in the angle and continuously releases medication as it slowly erodes. A new capsule/implant is inserted every 4 months.

Several phase 3 studies show a 30% decrease in IOP over a 12-week period, which is comparable to drops, Wood said.

Wroten said the product is tentatively planned for market in the first quarter of 2020.

“The Bimatoprost SR platform will probably be approved first because it’s the furthest along,” Brandt told OSN. “I suspect it will face the highest level of scrutiny by the FDA, because the FDA is very aware of safety concerns with injectable platforms being used in people with mild diseases. There will have to be a balance of efficacy vs. safety concerns that the FDA and its advisory panels will have to consider.”

“It’s not just simply replacing medication for 6 months, it’s much more than that, and I think you’ll love it,” Ahmed said at SECO. “This is really helping us address disease and adherence.”

Also for open-angle glaucoma, the iDose by Glaukos (travoprost) is a nondegradable titanium implant filled with a 6-month supply of travoprost anchored into the anterior chamber. The implant, which is in phase 3 trials, features a cap with a membrane, which allows for continual release of the medication.

The phase 2 trial showed a 30% IOP reduction, Wood said.

Another new platform, ENB515 travoprost ER, was acquired by Aerie Pharmaceuticals from Envisia. This technology features a biodegradeable rod-shaped nanoparticle with extended release of travoprost through intracameral injection.

The phase 2 study reported nearly a 25% IOP reduction.

OTX-TP by Ocular Therapeutics is an erodible travoprost implant currently in phase 3 trials. It is placed into the inferior or superior canalicula.

Evolute from Mati Therapeutics is a sustained delivery platform wherein a plug is inserted into the patient’s tear duct. Mati is in phase 2 trials with this technology.

The Bimatoprost ring (Allergan) is a periocular ring that is custom fit into the conjunctival cul-de-sac and releases preservative-free bimatoprost over a sustained period.

More than 80% of patients said the ring was comfortable or fairly comfortable. “The ring stayed in place in nine out of 10 patients for 6 months. Of those for whom it stayed in place, all but one said they could not tell it was there,” Wroten said.

Wroten said he is excited about Eyenovia’s MicroProst eye spray. “Eyenovia is appealing to me, as it’s something that could be easily adopted right off the bat,” he said.

The new microdrop drug delivery allows a patient to line up the device in front of their eye and push a button to release a 7-µL “spray,” which the company determined matches the average capacity of the fornix and reduces waste, Wroten said at SECO. Most droppers release 30 µL to 50 µL per drop.

MicroProst (microdose latanoprost with Optejet delivery) uses Eyenovia’s piezo-print delivery system technology to deliver microdoses of IOP-lowering medications, as reported by Ocular Surgery News.

Graybug Vision (Redwood City, Calif.) also has a therapy in the works, with a pipeline of subconjunctival injections of sustained-release medications “that looks promising,” according to Wroten.

Another technology in development is based on ultrasound. Two companies are using B-scan ophthalmic ultrasound to ablate the trabecular meshwork and ciliary body, similar to selective laser trabeculoplasty, without using a laser, Wroten explained.

EyeTechCare, Rillieux-la-Pape, France, is working on EYEOP1, and EyeSonix, in Long Beach, Calif., is developing Therapeutic Ultrasound for Glaucoma (TUG).

With a single administration of the therapy, 20% of patients who were studied saw a decrease in IOP with TUG, Wroten added.

Wood said that researchers at Massachusetts Eye and Ear in Boston distributed a questionnaire that quantified patient willingness to try a nontraditional glaucoma treatment regimen.

Out of 199 patients, 30% to 54% were willing to try alternative approaches such as intracameral injections, drug-eluting lenses and other nontraditional therapy – if they were the same price as topical drops.

“Even if we get this therapy, they may not be interested if it’s more expensive,” she said.

Patient adoption, scope of practice

“Glaucoma management is an important optometric role, and in 49 of the 50 states, optometrists manage it. There are a large number of patients to potentially benefit from these new platforms,” Wood said.

She added that understanding the new platforms is essential, even if they fall outside of optometry licensure. She sees optometry being extremely involved in these new devices and delivery methods.

“It would still be critical that we know how the device works, when it is used and how to follow up with the patient,” Wood said. “I see ODs and ophthalmologists working together to optimize patient care.”

A number of states provide the scope of practice for optometrists to deliver the sustained-release medication, Wroten said. “Several states are poised to do that now; others would require a change in their scope of practice and perhaps a change in their practice patterns to deliver some of the medications intraocularly. It is within the scope of optometry to be able to provide these therapies.”

Punctal plugs and the bimatoprost ring are certainly within optometry’s scope of practice, according to Murray Fingeret, OD, FAAO, a PCON Editorial Board Member. “The platforms are on the surface of the eye or in the puncta; optometrists can utilize them for their patients directly,” he said.

For patients who are not controlled, optometrists can recommend injections.

However, Fingeret reserves judgment on punctal plugs. “They’ve just been in development for so long. I’ll believe it when I see it, if they lower IOP enough,” he said.

“Punctal plugs seem like another reasonable solution, but they have been in the works for years,” Marrelli agreed.

She is concerned about patients on multiple medications and how extended release can truly benefit them. “An injectable pellet might take care of one of their medications. But are they going to get three pellets injected into their eye?” she asked.

At this point, Marrelli does not think sustained release therapy will be first-line therapy for most patients. “I think we will still be looking at eye drops,” she said.

As for platform adoption, Wroten said insurers will drive some of the adoption rates along with cost efficiency and therapy outcomes.

“At this point, we are seeing more and more limitations with formularies, as far as being dictated what we can prescribe for our patients with glaucoma. It might be a similar scenario here,” Wroten said. “An insurer decides what they want their first-line therapy to be, or the patient can pay an exorbitant fee otherwise.”

He added that it will be interesting to watch the products hit the market and independent studies free of bias be performed to help determine what makes the most sense for patients and their individual scenarios. He wondered whether pharmaceutical or surgical intervention will become standard of care.

“In these days of generic prostaglandins, will the insurer be willing to pay a significant premium with the idea of improved compliance but not necessarily IOP lowering?” Fingeret asked. “That’s the mystery no one knows the answer to right now.”

What sustained delivery means for glaucoma

Wood said the current problems with adherence to topical drops are vast. Common side effects include: red eyes, eyelash growth or eye color change, a bad taste in the mouth, loss of periocular fat, lethargy, blurred vision, and breathing issues or slowing of the heart rate with beta-blockers.

“I’m asking my patients to do a lot when I’m asking them to use these drops,” she said.

Furthermore, forgetfulness, especially within an older patient population, is a concern. Trouble with instillation is also an issue. Patients will get multiple drops in one eye and end up running out before the end of the prescription period. They also might have a tremor, trouble with their vision or other things that make using drops a challenge, Wood said.

Daily drop use can also cause patient anxiety, with the reminder of a potentially blinding eye disease every time they instill the drops.

Patients also lack any way of knowing whether the drops are working, except when they have an appointment and get their pressure readings, Wood continued.

The current paradigm is treatment via topical solutions, with glaucoma having a small share of the surgical pie, perhaps due to potential complications, Ahmed said during SECO.

Patient care would benefit from more treatment options in glaucoma.

Topical drops dissipate over time in the eye, while the same amount of medication is available with sustained release, contributing to the goal for less IOP variability. “The hope is for less IOP variability, less fluctuation in eye pressure,” Wood said.

She said previous studies have shown an increase in variability in IOP increases the risk in visual field progression.

“We have a crisis here. We aren’t treating the disease right,” Ahmed said.

Fingeret added that sustained release therapies allow for better IOP control and can preserve vision longer.

The recommendation of surgery in glaucoma could also change with the approval of new treatment platforms.

“If you’re able to control more patients without taking them to the operating room, I think that’s a benefit,” Marrelli said.

“You would hope that it would reduce the need for surgery,” Fingeret said, “while also allowing for better IOP control, stable pressures and preserving vision longer.

Future glaucoma treatment platforms are trying to optimize efficacy and minimize side effects, according to Wood.

Personalized medicine

Wroten noted that what is best for patient A is not necessarily best for patient B.

Marrelli agreed. “I don’t think we will ever be able to have a one-size-fits-all glaucoma therapy,” she said.

“As we are moving more and more into personalized medicine and gaining a better understanding of gene testing and genotyping to figure out how we can tailor our treatment to the individual,” Wroten said, “taking into consideration their disease as well as any other potential limitation to compliance allows us to be more effective doctors and get the outcomes we need.”

Optometry will see a significant reduction in vision loss from glaucoma with better pharmaceutical agents and better diagnostic devices, he added. Treating and assessing glaucoma earlier will continue to improve outcomes.

“The opportunity is now for disruption and innovation in the glaucoma space,” Ahmed said. – by Abigail Sutton

• References:
• Asrani, et al. J Glaucoma. 2000;(2);134-142.
• Cook, C; Foster, P. Can J Ophthalmol. 2012;doi.org/10.1016/j.jcjo.2012.02.003.
• Lee PP, et al. Arch Ophthalmol. 2006;doi:10.1001/archopht.124.1.12.
• Linnehan R. Alternative drug delivery platforms for glaucoma are coming. https://www.healio.com/ophthalmology/glaucoma/news/print/ocular-surgery-news/%7b22b3e048-f0f2-492b-b83f-8d7076f6396a%7d/alternative-drug-delivery-platforms-for-glaucoma-are-coming. Posted February 10, 2019.
• Sutton A. Glaucoma expert endorses ‘interventional glaucoma’ treatment. https://www.healio.com/optometry/glaucoma/news/online/%7B116fff13-bf85-4066-8829-eb1383d67899%7D/glaucoma-expert-endorses-interventional-glaucoma-treatment. Posted March 12, 2019.
• Sutton A. New drug delivery technologies may improve compliance in glaucoma patients. https://www.healio.com/optometry/glaucoma/news/online/%7B9b2311d9-c17c-4a86-93f7-ac2859dc5c9a%7D/new-drug-delivery-technologies-may-improve-compliance-in-glaucoma-patients. Posted March 20, 2019.
• Sutton A. New drugs, delivery methods in the pipeline for ocular surface, retina, glaucoma. https://www.healio.com/optometry/technology/news/online/%7B73e32c63-80c5-4a27-b776-f9521cb33d07%7D/new-drugs-delivery-methods-in-the-pipeline-for-ocular-surface-retina-glaucoma. Posted. March 8, 2019.
• Wang BB, et al. Digit J Ophthalmol. 2018;doi:10.5693/djo.01.2018.07.001.

• For more information:
• Ike K. Ahmed, MD, is medical director of Prism Eye Institute, Mississauga, Ontario. He can be reached at: ikeahmed@mac.com.
• James D. Brandt, MD, practices at UC Davis Eye Center, Sacramento, Calif. He can be reached at: jdbrandt@ucdavis.edu.
• Murray Fingeret, OD, FAAO, practices in Queens, N.Y., and can be reached at: murrayf@optonline.net.
• Danica Marrelli, OD, FAAO, DiplAAO, is clinical professor and assistant dean of clinical education at University of Houston College of Optometry. She can be reached at: DMarrelli@uh.edu.
• Sarah Dougherty Wood, OD, MS, FAAO, DiplABO, practices at Kellogg Eye Center, Ann Arbor, Mich. She can be reached at: skwood@med.mich.edu.
• Chris Wroten, OD, practices at Bond-Wroten Eye Clinic in southeast Louisiana. He can be reached at chris.wroten@bweyes.com.

Disclosures:Ahmed is a consultant for: Acucela, Aerie, Alcon, Allergan, ArcScan, Bausch + Lomb, Beaver Visitec, Carl Zeiss Meditec, Centervue, ElutiMed, Equinox, ForSight Labs, Glaukos, Gore, Iantech, InjectSense, Iridex, iStar, Ivantis, Johnson & Johnson, KeLoTec, LayerBio, Leica Microsystems, New World Medical, Omega Ophthalmics, PolyActiva, Sanoculis, Santen, SciencBased Health, Sight Sciences, Stroma, TrueVision and Vizzario. He receives research support from: Alcon, Allergan, ArcScan, Carl Zeiss Meditec, Glaukos, Iridex, Ivantis, Johnson & Johnson, New World Medical and speakers honorarium from: Carl Zeiss Meditec, Glaukos and Johnson & Johnson. Brandt reports he owns stock with Glaukos, is a consultant for Aerie Pharmaceuticals, has a consulting relationship with Allergan and is involved as the principle investigator with the phase 2 study for the Bimatoprost SR Ring when it was developed by the startup company ForSight Vision. Fingeret is a consultant for Allergan and Aerie Pharmaceuticals. Marrelli receives speaker or advisory board fees from Aerie, Allergan, Bausch + Lomb and Novartis. Wood was previously involved in the ARTEMIS study. Wroten reported no relevant financial disclosures.